Pharmaceutical composition, methods for treating and uses thereof

ABSTRACT

The present invention relates to certain SGLT-2 inhibitors for treating and/or preventing metabolic disorders, such as type 1 or type 2 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CKD).

TECHNICAL FIELD OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors for treatingand/or preventing metabolic disorders, such as type 2 or type 1 diabetesmellitus or pre-diabetes, in patients with renal impairment or chronickidney disease (CDK).

BACKGROUND OF THE INVENTION

Diabetes is a major public health problem, with a prevalence that isexpected to reach 552 million people worldwide by 2030. Type 2 diabetesmellitus (T2DM) accounts for 90% of all diabetes cases. Most medicationsfor the treatment of T2DM act through insulin-dependent mechanisms; theprogressive loss of beta-cell function that is characteristic of T2DMmeans that most patients with T2DM ultimately require multiple therapiesto maintain glycemic control.

Nephropathy is a well-established complication of poor glycemic controlin patients with diabetes. An estimated 10-36% of patients with T2DMhave some degree of renal impairment and chronic kidney disease (CKD) ispresent in approximately 40% of patients with diabetes. CKD has beenclassified into 5 stages, where stage 1 is kidney damage with normal GFR(mL/min/1.73 m²) of ≥90; stage 2 is kidney damage with a mild decreasein GFR (GFR 60-89); stage 3 is a moderate decrease in GFR (GFR 30-59);stage 4 is a severe decrease in GFR (GFR 15-29); and stage 5 is kidneyfailure (GFR <15 or dialysis). The use of a number of anti-diabetesagents is restricted in patients with renal impairment. Metformin iscontraindicated in patients with renal dysfunction due to the risk ofaccumulation and lactic acidosis. Caution is advised with the use ofinsulin secretagogues in renally impaired patients. The DPP-4 inhibitorssaxagliptin, sitagliptin and vildagliptin (but not linagliptin) arepredominantly excreted renally, so dose reduction is necessary inpatients with advanced chronic kidney disease.

There is therefore a need for methods, medicaments and pharmaceuticalcompositions for the treatment of metabolic disorders, such as type 2diabetes, in patients with renal impairment or chronic kidney disease(CDK).

SUMMARY OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing metabolicdisorders, such as type 2 diabetes mellitus, in patients with renalimpairment or chronic kidney disease (CDK).

Accordingly, in one embodiment, the present invention provides a methodfor using empagliflozin in one or more of the following methods:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder selected from the group consisting of type 2        diabetes mellitus, impaired glucose tolerance, impaired fasting        blood glucose, hyperglycemia, postprandial hyperglycemia,        hyperinsulinemia and metabolic syndrome; or    -   slowing the progression of, delaying or treating of        pre-diabetes; or    -   preventing, slowing the progression of, delaying or treating of        an onset of type 2 diabetes mellitus; or    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c; or    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance, impaired fasting blood glucose,        insulin resistance or from metabolic syndrome to type 2 diabetes        mellitus; or    -   preventing, slowing the progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus such as cataracts and micro-        and macrovascular diseases, such as nephropathy, retinopathy,        neuropathy, tissue ischaemia, diabetic foot, dyslipidemia,        arteriosclerosis, myocardial infarction, acute coronary        syndrome, unstable angina pectoris, stable angina pectoris,        stroke, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders and vascular restenosis;        or    -   reducing body weight and/or body fat, or preventing an increase        in body weight and/or body fat, or facilitating a reduction in        body weight and/or body fat; or    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or restoring the        functionality of pancreatic insulin secretion; or    -   preventing, slowing, delaying or treating diseases or conditions        attributed to an abnormal accumulation of ectopic fat, in        particular liver fat; or    -   for maintaining and/or improving the insulin sensitivity and/or        for treating or preventing hyperinsulinemia and/or insulin        resistance;        in a patient with renal impairment or chronic kidney disease        (CDK), in particular a patient with mild or moderate renal        impairment.

In one embodiment, the method comprises treating prediabetes, type 1 ortype 2 diabetes mellitus. In one embodiment, the method comprisesimproving glycemic control in a patient with prediabetes, type 1 or type2 diabetes mellitus.

Accordingly, in one embodiment, the present invention provides a methodof treating prediabetes, type 1 or type 2 diabetes mellitus in patientcomprising administering empagliflozin to the patient, wherein thepatient has moderate renal impairment. In one embodiment, the patienthas moderate A renal impairment. In one embodiment, the patient hasmoderate B renal impairment.

In one embodiment, the present invention further provides a method forimproving glycemic control in a patient with prediabetes, type 1 or type2 diabetes mellitus comprising administering empagliflozin to thepatient, wherein the patient has moderate renal impairment. In oneembodiment, the patient has moderate A renal impairment. In oneembodiment, the patient has moderate B renal impairment.

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus in patientcomprising administering empagliflozin to the patient, wherein thepatient has stage 3 chronic kidney disease (CKD). In one embodiment, thepatient has stage 3A chronic kidney disease (CKD). In one embodiment,the patient has stage 3B chronic kidney disease (CKD).

In one embodiment, the present invention further provides a method forimproving glycemic control in a patient with prediabetes, type 1 or type2 diabetes mellitus comprising administering empagliflozin to thepatient, wherein the patient has stage 3 chronic kidney disease (CKD).In one embodiment, the patient has stage 3A chronic kidney disease(CKD). In one embodiment, the patient has stage 3B chronic kidneydisease (CKD).

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus or improvingglycemic control in a patient with prediabetes, type 1 or type 2diabetes mellitus, said method comprising:

-   -   a) assessing the renal function of a patient;    -   b) treating a patient having moderate renal impairment with        empagliflozin, but not treating a patient having severe renal        impairment or kidney failure with empagliflozin.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function withempagliflozin.

In one embodiment, the present invention further provides a methodcomprising:

-   -   a) identifying a patient in need of treatment for type 2        diabetes mellitus;    -   b) assessing the renal function of said patient;    -   c) treating a patient having moderate renal impairment with        empagliflozin, but not treating a patient having severe renal        impairment or kidney failure with empagliflozin.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function withempagliflozin.

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus or improvingglycemic control in a patient with prediabetes, type 1 or type 2diabetes mellitus, said method comprising:

-   -   a) assessing the renal function of said patient;    -   b) treating a patient having moderate A renal impairment with        empagliflozin, but not treating a patient having moderate B        renal impairment, severe renal impairment or kidney failure with        empagliflozin.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function withempagliflozin.

In one embodiment, the present invention further provides a methodcomprising:

-   -   a) identifying a patient in need of treatment for type 2        diabetes mellitus;    -   b) assessing the renal function of said patient;    -   c) treating a patient having moderate A renal impairment with        empagliflozin, but not treating a patient having moderate B        renal impairment, severe renal impairment or kidney failure with        empagliflozin.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function withempagliflozin.

In one embodiment, the present invention further provides a method oftreating type 2 diabetes comprising:

-   -   a) determining the glomerular filtration rate (eGFR) of a        patient in need of treatment for prediabetes, type 1 or type 2        diabetes mellitus;    -   b) administering empagliflozin to the patient, if the eGFR of        the patient is ≥30 ml/min/1.73 m².

In one embodiment, empagliflozin is administered if the eGFR of thepatient is between ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m². In oneembodiment, the method further comprises discontinuing empagliflozin ifthe eGFR of the patient falls below 30 ml/min/1.73 m². In oneembodiment, empagliflozin is administered if the eGFR of the patient isbetween ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m². In one embodiment,the method further comprises discontinuing empagliflozin if the eGFR ofthe patient falls below 45 ml/min/1.73 m².

In one embodiment, the present invention further provides a methodcomprising:

-   -   a) assessing the renal function of a patient;    -   b) administering empagliflozin to the patient;    -   c) discontinuing empagliflozin if the eGFR of the patient falls        below 30 ml/min/1.73 m².

In one embodiment, empagliflozin is administered if the eGFR of thepatient is between ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides a methodcomprising:

-   -   a) assessing the renal function of a patient;    -   b) administering empagliflozin to the patient;    -   c) discontinuing empagliflozin if the eGFR of the patient falls        below 45 ml/min/1.73 m².

In one embodiment, empagliflozin is administered if the eGFR of thepatient is between ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus comprising:

-   -   a) determining that the eGFR of a patient in need of treatment        for type 2 diabetes mellitus is between ≥30 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   b) administering empagliflozin to the patient.

In one embodiment, the method further comprises discontinuingempagliflozin if the eGFR of the patient falls below 30 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus comprising:

-   -   a) determining that the eGFR of a patient in need of treatment        for type 2 diabetes mellitus is between ≥45 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   b) administering empagliflozin to the patient.

In one embodiment, the method further comprises discontinuingempagliflozin if the eGFR of the patient falls below 45 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus in a patienthaving an estimated glomerular filtration rate (eGFR) between ≥30ml/min/1.73 m² and <60 ml/min/1.73 m² comprising:

-   -   a) measuring the patient's estimated glomerular filtration rate        (eGFR)    -   b) measuring the effectiveness of empagliflozin for treatment of        prediabetes, type 1 or type 2 diabetes mellitus in said        patients; and    -   c) administering empagliflozin to the patient.

In one embodiment, the patient has a glomerular filtration rate (eGFR)between ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m². The effectiveness ofempagliflozin is for example measured by determining the % HbA1c of thefree plasma glucose (FPG) in the patient.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) determining that the patient's estimated glomerular        filtration rate (eGFR) is ≥30 ml/min/1.73 m²;    -   c) selecting a prediabetes, type 1 or type 2 diabetes mellitus        treatment for the patient that comprises the administration of        empagliflozin, based on the recognition that empagliflozin is        effective for treatment of type 2 diabetes mellitus in patients        whose eGFR is ≥30 ml/min/1.73 m² and not in patients whose eGFR        is <30 ml/min/1.73 m²; and    -   d) administering empagliflozin to the patient.

In one embodiment, step b) comprises determining that the patient'sestimated glomerular filtration rate (eGFR) is ≥30 ml/min/1.73 m² and<90 ml/min/1.73 m². In one embodiment, step b) comprises determiningthat the patient's estimated glomerular filtration rate (eGFR) is ≥30ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient with prediabetes, type 1 or type 2        diabetes mellitus in need of improvement of glycemic control;    -   b) determining that the patient's estimated glomerular        filtration rate (eGFR) is ≥30 ml/min/1.73 m²;    -   c) selecting a prediabetes, type 1 or type 2 diabetes mellitus        treatment for the patient that comprises the administration of        empagliflozin, based on the recognition that empagliflozin is        effective for treatment of prediabetes, type 1 or type 2        diabetes mellitus in patients whose eGFR is ≥30 ml/min/1.73 m²        and not in patients whose eGFR is <30 ml/min/1.73 m²; and    -   d) administering empagliflozin to the patient.

In one embodiment, step b) comprises determining that the patient'sestimated glomerular filtration rate (eGFR) is ≥30 ml/min/1.73 m² and<90 ml/min/1.73 m². In one embodiment, step b) comprises determiningthat the patient's estimated glomerular filtration rate (eGFR) is ≥30ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) measuring the patient's estimated glomerular filtration rate        (eGFR);    -   c) determining that the patient's eGFR is ≥30 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   d) prescribing a prediabetes, type 1 or type 2 diabetes mellitus        treatment for the patient that includes use of empagliflozin,        based on the recognition that empagliflozin is effective for        treatment of type 2 diabetes in patients whose eGFR is ≥30        ml/min/1.73 m² and not in patients whose eGFR is <30 ml/min/1.73        m²; and    -   e) administering empagliflozin to the patient.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) determining that the patient's eGFR is ≥30 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   c) selecting empagliflozin as a treatment for the patient based        on the recognition that empagliflozin is effective for treatment        of type 2 diabetes mellitus in patients who have an eGFR of ≥30        ml/min/1.73 m² but may lack efficacy in patients with eGFR <30        ml/min/1.73 m²;    -   d) administering a pharmaceutical composition comprising        empagliflozin to the patient;    -   e) determining during treatment with the pharmaceutical        composition that the patient's eGFR has dropped below 30        ml/min/1.73 m²; and    -   f) ceasing treatment of the patient with the pharmaceutical        composition, based on the recognition that empagliflozin may        lack efficacy in patients with eGFR <30 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) measuring the patient's estimated glomerular filtration rate        (eGFR);    -   c) determining that the patient's eGFR is ≥30 ml/min/1.73 m² and        <60 ml/min/1.73 m².    -   d) prescribing a type 2 diabetes treatment for the patient that        includes use of empagliflozin, based on the recognition that        empagliflozin is effective for treatment of type 2 diabetes in        patients whose eGFR is ≥30 ml/min/1.73 m² and not in patients        whose eGFR is <30 ml/min/1.73 m²; and    -   e) advising the patient to self-administer empagliflozin.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) treating the patient with a first treatment regimen that does        not comprise use of empagliflozin;    -   c) determining that the first treatment regimen does not provide        adequate glycemic control in the patient;    -   d) measuring the patient's estimated glomerular filtration rate        (eGFR);    -   e) determining that the patient's eGFR is ≥30 ml/min/1.73 m² and        <60 ml/min/1.73 m².    -   f) prescribing an altered treatment regimen for the patient that        includes use of empagliflozin, based on the recognition that        empagliflozin is effective for treatment of prediabetes, type 1        or type 2 diabetes mellitus in patients whose eGFR is ≥30        ml/min/1.73 m² and not in patients whose eGFR is <30 ml/min/1.73        m²;    -   g) advising the patient to administer empagliflozin daily as        part of the altered treatment regimen; and    -   h) confirming that the patient's glycemic control is improved on        the altered treatment regimen, compared to on the first        treatment regimen.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) determining that the patient's estimated glomerular        filtration rate (eGFR) is ≥45 ml/min/1.73 m² and <60 ml/min/1.73        m²;    -   c) selecting a type 2 diabetes treatment for the patient that        includes empagliflozin, based on the recognition that        empagliflozin is effective for treatment of prediabetes, type 1        or type 2 diabetes mellitus in patients whose eGFR is ≥45        ml/min/1.73 m² and not in patients whose eGFR is <45 ml/min/1.73        m²; and    -   d) administering empagliflozin to the patient.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) measuring the patient's estimated glomerular filtration rate        (eGFR);    -   c) determining that the patient's eGFR is ≥45 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   d) prescribing a prediabetes, type 1 or type 2 diabetes mellitus        treatment for the patient that includes use of empagliflozin,        based on the recognition that empagliflozin is effective for        treatment of type 2 diabetes mellitus in patients whose eGFR is        ≥45 ml/min/1.73 m² and not in patients whose eGFR is <45        ml/min/1.73 m²; and    -   e) administering empagliflozin to the patient.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) determining that the patient's eGFR is ≥45 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   c) selecting empagliflozin as a treatment for the patient based        on the recognition that empagliflozin is effective for treatment        of prediabetes, type 1 or type 2 diabetes mellitus in patients        who have an eGFR of ≥45 ml/min/1.73 m² but may lack efficacy in        patients with eGFR <45 ml/min/1.73 m²;    -   d) administering a pharmaceutical composition comprising        empagliflozin to the patient;    -   e) determining during treatment with the pharmaceutical        composition that the patient's eGFR has dropped below 45        ml/min/1.73 m²; and    -   f) ceasing treatment of the patient with the pharmaceutical        composition, based on the recognition that empagliflozin may        lack efficacy in patients with eGFR <45 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) measuring the patient's estimated glomerular filtration rate        (eGFR);    -   c) determining that the patient's eGFR is ≥45 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   d) prescribing a type 2 diabetes treatment for the patient that        includes use of empagliflozin, based on the recognition that        empagliflozin is effective for treatment of prediabetes, type 1        or type 2 diabetes mellitus in patients whose eGFR is ≥45        ml/min/1.73 m² and not in patients whose eGFR is <45 ml/min/1.73        m²; and    -   e) advising the patient to self-administer empagliflozin.

In one embodiment, the present invention further provides a method oftreatment comprising:

-   -   a) identifying a patient as being in need of treatment for        prediabetes, type 1 or type 2 diabetes mellitus;    -   b) treating the patient with a first treatment regimen that does        not comprise use of empagliflozin;    -   c) determining that the first treatment regimen does not provide        adequate glycemic control in the patient;    -   d) measuring the patient's estimated glomerular filtration rate        (eGFR);    -   e) determining that the patient's eGFR is ≥45 ml/min/1.73 m² and        <60 ml/min/1.73 m²;    -   f) prescribing an altered treatment regimen for the patient that        includes use of empagliflozin, based on the recognition that        empagliflozin is effective for treatment of prediabetes, type 1        or type 2 diabetes mellitus in patients whose eGFR is ≥45        ml/min/1.73 m² and not in patients whose eGFR is <45 ml/min/1.73        m²;    -   g) advising the patient to administer empagliflozin daily as        part of the altered treatment regimen; and    -   h) confirming that the patient's glycemic control is improved on        the altered treatment regimen, compared to on the first        treatment regimen.

In one embodiment, in any one of the methods above empagliflozin isadministered as a pharmaceutical composition, for example a tablet. Inone embodiment, the pharmaceutical composition comprises 10 mg or 25 mgof empagliflozin. In one embodiment, empagliflozin is administered oncedaily.

In one embodiment, the present invention further provides a method ofimprovement of glycemic control in a patient with prediabetes, type 1 ortype 2 diabetes mellitus, wherein the patient's estimated glomerularfiltration rate (eGFR) is ≥30 ml/min/1.73 m² comprising theadministration of a pharmaceutical composition comprising empagliflozinto the patient. In one embodiment, the patient's estimated glomerularfiltration rate (eGFR) is ≥45 ml/min/1.73 m². In one embodiment, thepresent invention further provides a method of improvement of glycemiccontrol in a type 2 diabetes mellitus patient with moderate renalimpairment comprising the administration of a pharmaceutical compositioncomprising empagliflozin to the patient. In one embodiment, the patientis with moderate A renal (CKD stage 3A) impairment. In one embodiment,the patient is with moderate B renal (CKD stage 3B) impairment. In oneembodiment, the pharmaceutical composition comprises 10 mg or 25 mg ofempagliflozin. In one embodiment, empagliflozin is administered oncedaily.

In one embodiment, the present invention further provides empagliflozinfor use in the treatment of prediabetes, type 1 or type 2 diabetesmellitus in a patient wherein the patient's estimated glomerularfiltration rate (eGFR) is ≥30 ml/min/1.73 m².

In one embodiment, the present invention further provides apharmaceutical composition comprising empagliflozin for use in thetreatment of prediabetes, type 1 or type 2 diabetes mellitus in apatient wherein the patient's estimated glomerular filtration rate(eGFR) is ≥30 ml/min/1.73 m².

In one embodiment, the present invention further provides empagliflozinfor use in the improvement of glycemic control in a patient withprediabetes, type 1 or type 2 diabetes mellitus wherein the patient'sestimated glomerular filtration rate (eGFR) is ≥30 ml/min/1.73 m².

In one embodiment, the present invention further provides apharmaceutical composition comprising empagliflozin for use in theimprovement of glycemic control in a patient with prediabetes, type 1 ortype 2 diabetes mellitus wherein the patient's estimated glomerularfiltration rate (eGFR) is ≥30 ml/min/1.73 m².

In one embodiment, in any of the use of empagliflozin or apharmaceutical composition above, the patient's estimated glomerularfiltration rate (eGFR) is ≥30 ml/min/1.73 m² and <90 ml/min/1.73 m². Inone embodiment, the patient's estimated glomerular filtration rate(eGFR) is ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m². In one embodiment,the patient's estimated glomerular filtration rate (eGFR) is ≥45ml/min/1.73 m². In one embodiment, the patient's estimated glomerularfiltration rate (eGFR) is ≥45 ml/min/1.73 m² and <90 ml/min/1.73 m². Inone embodiment, the patient's estimated glomerular filtration rate(eGFR) is ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides empagliflozinfor use in the treatment of prediabetes, type 1 or type 2 diabetesmellitus in a patient with moderate renal impairment. In one embodiment,the present invention provides a pharmaceutical composition comprisingempagliflozin for use in the treatment of prediabetes, type 1 or type 2diabetes mellitus in a patient with moderate renal impairment. In oneembodiment, the present invention provides empagliflozin for use in theimprovement of glycemic control in a prediabetes, type 1 or type 2diabetes mellitus patient with moderate renal impairment. In oneembodiment, the present invention provides a pharmaceutical compositioncomprising empagliflozin for use in the improvement of glycemic controlin a prediabetes, type 1 or type 2 diabetes mellitus patient withmoderate renal impairment.

In one embodiment, in any use of empagliflozin or a pharmaceuticalcomposition above, the patient is with moderate A renal impairment orwith moderate B renal impairment. In one embodiment, the use is as anadjunct to diet and exercise. In one embodiment, the patient is an adultpatient. In one embodiment, the use is once daily. In one embodiment,the use is 10 mg or 25 mg once daily.

In a further aspect of the present invention, empagliflozin isadministered orally, for example in a total daily amount of 10 mg or 25mg. In one embodiment, empagliflozin is administering as apharmaceutical composition comprising 10 mg or 25 mg of empagliflozin,for example as a tablet.

In one aspect of the present invention, in a method or use disclosedherein a patient is patient with type 2 diabetes mellitus (or type 2diabetes mellitus patient), a patient treated for type 2 diabetesmellitus, a patient diagnosed with type 2 diabetes mellitus or a patientin need of treatment for type 2 diabetes mellitus. In one aspect, apatient is a patient with pre-diabetes.

In a further aspect of the present invention, in a method or use asdescribed herein empagliflozin is administered to a patient at astarting dose of 10 mg daily, for example to a patient as describedherein. In one aspect, the dose of empagliflozin is increased to 25 mgdaily, for example if the patient requires additional glycemic control.Accordingly, in a further aspect, the present invention provides amethod or use as described herein comprising a) administering to apatient 10 mg of empagliflozin daily, b) determining that the patientrequires additional glycemic control and c) administering to the patient25 mg of empagliflozin daily.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering to a patient 10 mg ofempagliflozin daily, b) determining that the patient requires additionalglycemic control and c) administering to the patient 25 mg ofempagliflozin daily.

In a further aspect of the present invention, in a method or usedescribed herein empagliflozin is administered to a patient at astarting dose of 10 mg daily, for example to a patient having an eGFR≥30 ml/min/1.73 m² or to a patient having an eGFR ≥45 ml/min/1.73 m². Inone aspect, in said method or use, the dose is increased to 25 mg daily,for example if the patient requires additional glycemic control. In oneaspect, the dose of empagliflozin is increased to 25 mg daily in apatient having an eGFR ≥30 ml/min/1.73 m², in a patient having an eGFR≥45 ml/min/1.73 m² or in a patient having an eGFR ≥60 ml/min/1.73 m².

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥30 ml/min/1.73 m² and b) increasing the doseof empagliflozin administered to the patient to 25 mg daily in a patienthaving an eGFR ≥30 ml/min/1.73 m². In one aspect, said patient in stepa) requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥30 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥30 ml/min/1.73 m² and c) administering 25 mg ofempagliflozin daily to the patient. In one aspect, step b) furthercomprises determining that the patient requires additional glycemiccontrol.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥30 ml/min/1.73 m² and b) increasing the doseof empagliflozin administered to the patient to 25 mg daily in a patienthaving an eGFR ≥45 ml/min/1.73 m². In one aspect, said patient in stepa) requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥30 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥45 ml/min/1.73 m² and c) administering 25 mg ofempagliflozin daily to the patient. In one aspect, step b) furthercomprises determining that the patient requires additional glycemiccontrol.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥30 ml/min/1.73 m² and b) increasing the doseof empagliflozin administered to the patient to 25 mg daily in a patienthaving an eGFR ≥60 ml/min/1.73 m². In one aspect, said patient in stepa) requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥30 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥60 ml/min/1.73 m² and c) administering 25 mg ofempagliflozin daily to the patient. In one aspect, step b) furthercomprises determining that the patient requires additional glycemiccontrol.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥45 ml/min/1.73 m² and b) increasing the doseof empagliflozin administered to the patient to 25 mg daily in a patienthaving an eGFR ≥45 ml/min/1.73 m². In one aspect, said patient in stepa) requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥45 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥45 ml/min/1.73 m² and c) administering 25 mg ofempagliflozin daily to the patient. In one aspect, step b) furthercomprises determining that the patient requires additional glycemiccontrol.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥45 ml/min/1.73 m² and b) increasing the doseof empagliflozin administered to the patient to 25 mg daily in a patienthaving an eGFR ≥60 ml/min/1.73 m². In one aspect, said patient in stepa) requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥45 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥60 ml/min/1.73 m² and c) administering 25 mg ofempagliflozin daily to the patient. In one aspect, step b) furthercomprises determining that the patient requires additional glycemiccontrol.

In a further embodiment, in a method or use described hereinempagliflozin is administered to a patient at a dose of 10 mg daily to apatient having an eGFR ≥60 ml/min/1.73 m² and the patient continues tobe administered empagliflozin at a dose of 10 mg daily if the patient'seGFR is reduced to ≥30 to <60 ml/min/1.73 m² or to ≥45 to <60ml/min/1.73 m². Accordingly, in one aspect, the present inventionprovides a method of improving glycemic control in a patient with type 2diabetes mellitus, said method comprising a) administering 10 mg ofempagliflozin daily to a patient having an eGFR ≥60 ml/min/1.73 m², b)determining that the patient has an eGFR ≥30 to <60 ml/min/1.73 m² andc) continuing to administer 10 mg of empagliflozin daily to the patient.In an another aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥60 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥45 to <60 ml/min/1.73 m² and c) continuing toadminister 10 mg of empagliflozin daily to the patient.

In a further embodiment, in a method or use described hereinempagliflozin is administered to a patient at a starting dose of 10 mgdaily to a patient having an eGFR ≥60 ml/min/1.73 m², the dose ofempagliflozin is increased to 25 mg daily, for example if the patientrequires additional glycemic control, and the dose of empagliflozinadministered to the patient stays at a dose of 25 mg daily if thepatient's eGFR is reduced to ≥30 to <60 ml/min/1.73 m² or to ≥45 to <60ml/min/1.73 m². Accordingly, in one aspect, the present inventionprovides a method of improving glycemic control in a patient with type 2diabetes mellitus, said method comprising a) administering 10 mg ofempagliflozin daily to a patient having an eGFR ≥60 ml/min/1.73 m², b)increasing the dose of empagliflozin administered to the patient to 25mg daily, for example if the patient requires additional glycemiccontrol, c) determining that the patient has an eGFR ≥30 to <60ml/min/1.73 m² and d) administering 25 mg of empagliflozin daily to thepatient. In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥60 ml/min/1.73 m², b) increasing the dose ofempagliflozin administered to the patient to 25 mg daily, for example ifthe patient requires additional glycemic control, c) determining thatthe patient has an eGFR ≥45 to <60 ml/min/1.73 m² and d) administering25 mg empagliflozin daily to the patient.

In a further embodiment, in a method or use described hereinempagliflozin is administered to a patient at a starting dose of 10 mgdaily to a patient having an eGFR ≥60 ml/min/1.73 m², the dose ofempagliflozin is increased to 25 mg daily, for example if the patientrequires additional glycemic control, and the dose of empagliflozinadministered to the patient is reduced to a dose of 10 mg daily if thepatient's eGFR is reduced to ≥30 to <60 ml/min/1.73 m² or to ≥45 to <60ml/min/1.73 m². Accordingly, in one aspect, the present inventionprovides a method of improving glycemic control in a patient with type 2diabetes mellitus, said method comprising a) administering 10 mg ofempagliflozin daily to a patient having an eGFR ≥60 ml/min/1.73 m², b)increasing the dose of empagliflozin administered to the patient to 25mg daily, for example if the patient requires additional glycemiccontrol, c) determining that the patient has an eGFR ≥30 to <60ml/min/1.73 m² and d) administering 10 mg of empagliflozin daily to thepatient. In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 10 mg of empagliflozin daily toa patient having an eGFR ≥60 ml/min/1.73 m², b) increasing the dose ofempagliflozin administered to the patient to 25 mg daily, for example ifthe patient requires additional glycemic control, c) determining thatthe patient has an eGFR ≥45 to <60 ml/min/1.73 m² and d) administering10 mg of empagliflozin daily to the patient.

In one aspect, in any one of the methods of uses described above,empagliflozin is administered once daily to a patient, i.e. for example10 mg or 25 mg of empagliflozin is administered once daily to a patient.

In one aspect of the present invention, empagliflozin is administeredwith one or more other antidiabetic substances. In one embodiment, theother antidiabetic substances are selected from metformin,sulphonylureas, nateglinide, repaglinide, thiazolidinediones,PPARalpha-glucosidase inhibitors, insulin and insulin analogues, GLP-1and GLP-1 analogues and DPP-4 inhibitors. In one aspect, the presentinvention comprises administering empagliflozin in combination withmetformin and/or a DPP-4 inhibitor, for example linagliptin.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use as amedicament in any one of the methods described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use in thetreatment of any one of the diseases or conditions described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use in themanufacture of a medicament for use in any one of the methods describedherein.

Definitions

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor according to thepresent invention. An “active ingredient is also sometimes referred toherein as an “active substance”.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The terms “obesity” or “being obese” and the like are defined as thecondition wherein the individual has a BMI equal to or greater than 30kg/m². According to a WHO definition the term obesity may be categorizedas follows: the term “class I obesity” is the condition wherein the BMIis equal to or greater than 30 kg/m² but lower than 35 kg/m²; the term“class II obesity” is the condition wherein the BMI is equal to orgreater than 35 kg/m² but lower than 40 kg/m²; the term “class IIIobesity” is the condition wherein the BMI is equal to or greater than 40kg/m².

The indication obesity includes in particular exogenic obesity,hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity,hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity,symptomatic obesity, infantile obesity, upper body obesity, alimentaryobesity, hypogonadal obesity, central obesity, visceral obesity,abdominal obesity

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference ≥85 cm in men and ≥90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range, in particularbelow 70 mg/dL (3.89 mmol/L).

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e.the 2 hour postprandial blood glucose or serum glucose concentration canbe measured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(SuppL1): A459) and to an euglycemic clamp study. In addition, plasmaadiponectin levels can be monitored as a potential surrogate of insulinsensitivity. The estimate of insulin resistance by the homeostasisassessment model (HOMA)-IR score is calculated with the formula (GalvinP, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

Insulin resistance can be confirmed in these individuals by calculatingthe HOMA-IR score. For the purpose of this invention, insulin resistanceis defined as the clinical condition in which an individual has aHOMA-IR score >4.0 or a HOMA-IR score above the upper limit of normal asdefined for the laboratory performing the glucose and insulin assays.

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or IFG or type 2 diabetes.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detected,this is a particularly strong indication of the presence ofpre-diabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as a healthyperson, without this resulting in any clinical symptoms.

“Pre-diabetes” is a general term that refers to an intermediate stagebetween normal glucose tolerance (NGT) and overt type 2 diabetesmellitus (T2DM), also referred to as intermediate hyperglycaemia. Assuch, it represents 3 groups of individuals, those with impaired glucosetolerance (IGT) alone, those with impaired fasting glucose (IFG) aloneor those with both IGT and IFG. IGT and IFG usually have distinctpathophysiologic etiologies, however also a mixed condition withfeatures of both can exist in patients. Therefore in the context of thepresent invention a patient being diagnosed of having “pre-diabetes” isan individual with diagnosed IGT or diagnosed IFG or diagnosed with bothIGT and IFG. Following the definition according to the American DiabetesAssociation (ADA) and in the context of the present invention a patientbeing diagnosed of having “pre-diabetes” is an individual with:

a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1mg/dL=0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration,measured by a 75-g oral glucose tolerance test (OGTT), ranging between≥140 mg/dL and <200 mg/dL (i.e., IGT); orb) a fasting plasma glucose (FPG) concentration between ≥100 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT) of <140 mg/dL (i.e., IFG); orc) a fasting plasma glucose (FPG) concentration between ≥100 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT), ranging between 140 mg/dL and<200 mg/dL (i.e., both IGT and IFG).

Patients with “pre-diabetes” are individuals being pre-disposed to thedevelopment of type 2 diabetes. Pre-diabetes extends the definition ofIGT to include individuals with a fasting blood glucose within the highnormal range ≥100 mg/dL (J. B. Meigs, et al. Diabetes 2003;52:1475-1484). The scientific and medical basis for identifyingpre-diabetes as a serious health threat is laid out in a PositionStatement entitled “The Prevention or Delay of Type 2 Diabetes” issuedjointly by the American Diabetes Association and the National Instituteof Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002;25:742-749).

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index forbeta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl. 1): A459), the insulin/C-peptide secretion after an oralglucose tolerance test or a meal tolerance test, or by employing ahyperglycemic clamp study and/or minimal modeling after a frequentlysampled intravenous glucose tolerance test (Stumvoll et al., Eur J ClinInvest 2001, 31: 380-81).

The term “type 1 diabetes” is defined as the condition in which asubject has, in the presence of autoimmunity towards the pancreaticbeta-cell or insulin, a fasting blood glucose or serum glucoseconcentration greater than 125 mg/dL (6.94 mmol/L). If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach, in thepresence of autoimmunity towards the pancreatic beta cell or insulin. Ina glucose tolerance test 75 g of glucose are administered orally to thepatient being tested after 10-12 hours of fasting and the blood sugarlevel is recorded immediately before taking the glucose and 1 and 2hours after taking it. The presence of autoimmunity towards thepancreatic beta-cell may be observed by detection of circulating isletcell autoantibodies [“type 1A diabetes mellitus”], i.e., at least oneof: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm],IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like proteinIA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs ofautoimmunity without the presence of typical circulating autoantibodies[type 1B diabetes], i.e. as detected through pancreatic biopsy orimaging). Typically a genetic predisposition is present (e.g. HLA, INSVNTR and PTPN22), but this is not always the case.

The term “type 2 diabetes mellitus” or “T2DM” is defined as thecondition in which a subject has a fasting blood glucose or serumglucose concentration greater than 125 mg/dL (6.94 mmol/L). Themeasurement of blood glucose values is a standard procedure in routinemedical analysis. If a glucose tolerance test is carried out, the bloodsugar level of a diabetic will be in excess of 200 mg of glucose per dL(11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken onan empty stomach. In a glucose tolerance test 75 g of glucose areadministered orally to the patient being tested after 10-12 hours offasting and the blood sugar level is recorded immediately before takingthe glucose and 1 and 2 hours after taking it. In a healthy subject, theblood sugar level before taking the glucose will be between 60 and 110mg per dL of plasma, less than 200 mg per dL 1 hour after taking theglucose and less than 140 mg per dL after 2 hours. If after 2 hours thevalue is between 140 and 200 mg, this is regarded as abnormal glucosetolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference 85 cm in men and 90 cm in women;    -   2. Triglycerides: ≥150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≥130/85 mm Hg (SBP ≥130 or DBP ≥85)    -   5. Fasting blood glucose ≥100 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor and Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis suffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The term “glomerular filtration rate (GFR)” is defined as the volume offluid filtered from the renal (kidney) glomerular capillaries into theBowman's capsule per unit time. It is indicative of overall kidneyfunction. The glomerular filtration rate (GFR) can be calculated bymeasuring any chemical that has a steady level in the blood, and isfreely filtered but neither reabsorbed nor secreted by the kidneys. Therate therefore measured is the quantity of the substance in the urinethat originated from a calculable volume of blood. The GFR is typicallyrecorded in units of volume per time, e.g., milliliters per minute andthe formula below can be used:

GFR=(Urine Concentration×Urine Volume)/Plasma Concentration

The GFR can be determined by injecting inulin into the plasma. Sinceinulin is neither reabsorbed nor secreted by the kidney after glomerularfiltration, its rate of excretion is directly proportional to the rateof filtration of water and solutes across the glomerular filter. Anormal value is: GFR=90-125 mL/min/1.73 m², in particular GFR=100-125mL/min/1.73 m².

Other principles to determine GFR involve measuring 51Cr-EDTA,[125I]iothalamate or iohexol.

The “estimated glomerular filtration rate (eGFR)” is defined as derivedat screening from serum creatinine values based on e.g., the ChronicKidney Disease Epidemiology Collaboration (CKD-EPI) equation, theCockcroft-Gault formula or the Modification of Diet in Renal Disease(MDRD) formula, which are all known in the art.

The term “empagliflozin” refers to the SGLT2 inhibitor1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneof the formula

as described for example in WO 2005/092877. Methods of synthesis aredescribed in the literature, for example WO 06/120208 and WO2011/039108. According to this invention, it is to be understood thatthe definition of empagliflozin also comprises its hydrates, solvatesand polymorphic forms thereof, and prodrugs thereof. An advantageouscrystalline form of empagliflozin is described in WO 2006/117359 and WO2011/039107 which hereby are incorporated herein in their entirety. Thiscrystalline form possesses good solubility properties which enables agood bioavailability of the SGLT2 inhibitor. Furthermore, thecrystalline form is physico-chemically stable and thus provides a goodshelf-life stability of the pharmaceutical composition. Preferredpharmaceutical compositions, such as solid formulations for oraladministration, for example tablets, are described in WO 2010/092126,which hereby is incorporated herein in its entirety.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventivally treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

The term “tablet” comprises tablets without a coating and tablets withone or more coatings. Furthermore the “term” tablet comprises tabletshaving one, two, three or even more layers and press-coated tablets,wherein each of the beforementioned types of tablets may be without orwith one or more coatings. The term “tablet” also comprises mini, melt,chewable, effervescent and orally disintegrating tablets.

The terms “pharmacopoe” and “pharmacopoeias” refer to standardpharmacopoeias such as the “USP 31-NF 26 through Second Supplement”(United States Pharmacopeial Convention) or the “European Pharmacopoeia6.3” (European Directorate for the Quality of Medicines and Health Care,2000-2009).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A-C: Change from baseline in HbA_(1c) fasting plasma glucose(FPG), weight and blood pressure (BP) at week 24 in patients with renalimpairment treated with empagliflozin versus placebo.

FIG. 2: Pharmacokinetic and pharmacodynamic parameters for empagliflozinafter administration of a single oral 50 mg dose in patients with renalimpairment.

FIG. 3: Relative bioavailability of empagliflozin (50 mg qd) in subjectswith impaired renal function compared with subjects with normal renalfunction (n=40).

FIG. 4 A-D: Exposure to a single oral 50 mg dose of empagliflozin insubjects with normal and impaired renal function. (A) and (B) Meanplasma concentration-time profiles (insert: semi-log plot) (n=40). (C)AUC_(0-∞) and (D) C_(max); midline of boxes are medians, and boundariesare 25th and 75th percentiles; whiskers are the standard span for thequartiles (1.5×interquartile range).

FIG. 5 A-C: (A) CL_(R) from 0-96 h; (B) AUC_(0-∞), and (C) cumulativeamount of glucose excreted in urine in 24 h versus estimated glomerularfiltration rate after administration of a single oral 50 mg dose insubjects with normal and impaired renal function (n=40).

FIG. 6: Mean cumulative amounts of glucose excreted in urine afteradministration of a single oral 50 mg dose in subjects with normal andimpaired renal function (n=31).

FIG. 7 A-D: Change from baseline in HbA_(1c) fasting plasma glucose(FPG), weight and blood pressure (BP) at week 52 in patients with Type 2Diabetes Mellitus (T2DM) and Stage 3A, 3B and 4 Chronic Kidney Disease(CKD) treated with empagliflozin versus placebo.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing a metabolicdisorder, in particular type 1 or type 2 diabetes or pre-diabetes and/ordiseases related thereto (e.g. diabetic complications), in patients withrenal impairment or chronic kidney disease (CKD). In one aspect, thepresent invention relates to certain SGLT-2 inhibitors, in particularempagliflozin, for improving glycemic control in patient with type 1 ortype 2 diabetes or pre-diabetes and with renal impairment or chronickidney disease (CKD).

The treatment of type 2 diabetes typically begins with diet andexercise, followed by oral antidiabetic monotherapy, and althoughconventional monotherapy may initially control blood glucose in somepatients, it is however associated with a high secondary failure rate.The limitations of single-agent therapy for maintaining glycemic controlmay be overcome, at least in some patients, and for a limited period oftime by combining multiple drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required. But, because type 2 diabetes is a progressive disease,even patients with good initial responses to conventional combinationtherapy will eventually require an increase of the dosage or furthertreatment with insulin because the blood glucose level is very difficultto maintain stable for a long period of time. Although existingcombination therapy has the potential to enhance glycemic control, it isnot without limitations (especially with regard to long term efficacy).Further, traditional therapies may show an increased risk for sideeffects, such as hypoglycemia or weight gain, which may compromise theirefficacy and acceptability.

Thus, for many patients, these existing drug therapies result inprogressive deterioration in metabolic control despite treatment and donot sufficiently control metabolic status especially over long-term andthus fail to achieve and to maintain glycemic control in advanced orlate stage type 2 diabetes, including diabetes with inadequate glycemiccontrol despite conventional oral or non-oral antidiabetic medication.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with type 2 diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of conventionalantihyperglycemic therapies.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and makrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications such as e.g. myocardial infarction, stroke or vascularmortality or morbidity) in patients with type 2 diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and α-glucosidaseinhibitors.

Non-oral (typically injected) antidiabetic drugs conventionally used intherapy (such as e.g. first- or second-line, and/or mono- or (initial oradd-on) combination therapy) include, without being restricted thereto,GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemicagents can be associated with various adverse effects. For example,metformin can be associated with lactic acidosis or gastrointestinalside effects; sulfonylureas, glinides and insulin or insulin analoguescan be associated with hypoglycemia and weight gain; thiazolidinedionescan be associated with edema, bone fracture, weight gain and heartfailure/cardiac effects; and alpha-glucosidase blockers and GLP-1 orGLP-1 analogues can be associated with gastrointestinal adverse effects(e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting) and,most seriously (but rare), pancreatitis.

Type 1 diabetes mellitus (Type 1 diabetes), also called insulindependent diabetes mellitus or juvenile diabetes, is a form of diabetesmellitus that results from autoimmune destruction of insulin-producingbeta cells of the pancreas. The subsequent lack of insulin leads toincreased blood glucose concentrations and increased urinary glucoseexcretion. The classical symptoms are polyuria, polydipsia, polyphagia,and weight loss. Type 1 diabetes may be fatal unless treated withinsulin. Complications from type I diabetes are the same or similar tocomplications from type 2 diabetes. Standard therapy of type 1 diabetesis insulin treatment. Therapies for type 1 diabetes are for exampledescribed in WO 2012/062698.

SGLT2 inhibitors (sodium-glucose co-transporter 2) represent a novelclass of agents that are being developed for the treatment orimprovement in glycemic control in patients with type 2 diabetes.Glucopyranosyl-substituted benzene derivative are described as SGLT2inhibitors, for example in WO 01/27128, WO 03/099836, WO 2005/092877, WO2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. Theglucopyranosyl-substituted benzene derivatives are proposed as inducersof urinary sugar excretion and as medicaments in the treatment ofdiabetes.

Renal filtration and reuptake of glucose contributes, among othermechanisms, to the steady state plasma glucose concentration and cantherefore serve as an antidiabetic target. Reuptake of filtered glucoseacross epithelial cells of the kidney proceeds via sodium-dependentglucose cotransporters (SGLTs) located in the brush-border membranes inthe tubuli along the sodium gradient. There are at least 3 SGLT isoformsthat differ in their expression pattern as well as in theirphysico-chemical properties. SGLT2 is exclusively expressed in thekidney, whereas SGLT1 is expressed additionally in other tissues likeintestine, colon, skeletal and cardiac muscle. SGLT3 has been found tobe a glucose sensor in interstitial cells of the intestine without anytransport function. Potentially, other related, but not yetcharacterized genes, may contribute further to renal glucose reuptake.Under normoglycemia, glucose is completely reabsorbed by SGLTs in thekidney, whereas the reuptake capacity of the kidney is saturated atglucose concentrations higher than 10 mM, resulting in glucosuria(“diabetes mellitus”). This threshold concentration can be decreased bySGLT2-inhibition. It has been shown in experiments with the SGLTinhibitor phlorizin that SGLT-inhibition will partially inhibit thereuptake of glucose from the glomerular filtrate into the blood leadingto a decrease in blood glucose concentration and to glucosuria.

Empagliflozin is a novel SGLT2 inhibitor that is described for thetreatment or improvement in glycemic control in patients with type 2diabetes mellitus, for example in WO 05/092877, WO 06/117359, WO06/120208, WO 2010/092126, WO 2010/092123, WO 2011/039107, WO2011/039108.

Accordingly, in a particular embodiment, a SGLT-2 inhibitor within themeaning of this invention is empagliflozin.

The present invention relates to a therapeutic (treatment or prevention)method as described herein, said method comprising administering aneffective amount of a SGLT-2 inhibitor as described herein and,optionally, one or more other active or therapeutic agents as describedherein to a patient with renal impairment.

Patients with renal disease, renal dysfunction or renal impairment mayinclude patients with chronic renal insufficiency or impairment, whichcan be stratified (if not otherwise noted) according to glomerularfiltration rate (GFR, ml/min/1.73 m²) into 5 disease stages: stage 1characterized by normal GFR ≥90 plus either persistent albuminuria (e.g.UACR ≥30 mg/g) or known structural or hereditary renal disease; stage 2characterized by mild reduction of GFR (GFR 60-89) describing mild renalimpairment; stage 3 characterized by moderate reduction of GFR (GFR30-59) describing moderate renal impairment; stage 4 characterized bysevere reduction of GFR (GFR 15-29) describing severe renal impairment;and terminal stage 5 characterized by requiring dialysis or GFR <15describing established kidney failure (end-stage renal disease, ESRD).

Accordingly, chronic kidney disease and its stages (CKD 1-5) can beusually characterized or classified accordingly, such as based on thepresence of either kidney damage (albuminuria) or impaired estimatedglomerular filtration rate (GFR <60 [ml/min/1.73 m²], with or withoutkidney damage).

For the purpose of the present invention, the degree of renal impairmentin a patient is defined by the following estimated glomerular filtrationrate (eGFR):

Normal renal function: eGFR ≥90 ml/min/1.73 m²Mild renal impairment: eGFR ≥60 to <90 ml/min/1.73 m²Moderate renal impairment: eGFR ≥30 to <60 ml/min/1.73 m²Severe renal impairment: eGFR ≥15 to <30 ml/min/1.73 m²Kidney failure: eGFR <15 ml/min/1.73 m²

Accordingly, in the context of the present invention, a patient withnormal renal function has an eGFR ≥90 ml/min/1.73 m², a patient withmild renal impairment has an eGFR ≥60 to <90 ml/min/1.73 m², a patientwith moderate renal impairment has an eGFR ≥30 to <60 ml/min/1.73 m², apatient with severe renal impairment has an eGFR ≥15 to <30 ml/min/1.73m², a patient with kidney failure has an eGFR <15 ml/min/1.73 m².

According to the present invention moderate renal impairment can befurther divided into two sub-stages:

Moderate A renal impairment (CKD 3A): eGFR ≥45 to <60 ml/min/1.73 m²Moderate B renal impairment (CKD 3B): eGFR ≥30 to <45 ml/min/1.73 m²

Accordingly, in the context of the present invention, a patient withmoderate A renal impairment has an eGFR ≥45 to <60 ml/min/1.73 m² and apatient with moderate B renal impairment has an eGFR ≥30 to <45ml/min/1.73 m².

For the purpose of the present invention, the estimated glomerularfiltration rate (eGFR) is derived from the serum creatinine (SCr) valuebased on the MDRD formula below:

eGFR (mL/min/1.73m2)=175×[SCr (μmol/L)/88.4]−1.154×[age]−0.203×[0.742 ifpatient is female]×[1.212 if patient is of African origin]

For additional analyses, renal function can also be classified by theestimated creatinine clearance rate (eCCr) value, based on theCockcroft-Gault formula below:

eCCr (mL/min)=(140−age)×(weight in kg)×[0.85 if patient isfemale]/(72×SCr (mg/dL))

Renal function classification based on eCCr is similar to the eGFRclassification: normal renal function (≥90 mL/min), mild impairment (60to <90 mL/min), moderate impairment (30 to <60 mL/min), and severeimpairment (≥15 to <30 mL/min).

Generally, mild renal impairment according to the present inventioncorresponds to stage 2 chronic kidney disease, moderate renal impairmentaccording to the present invention generally corresponds to stage 3chronic kidney disease, and severe renal impairment according to thepresent invention generally corresponds to stage 4 chronic kidneydisease. Likewise, moderate A renal impairment according to the presentinvention generally corresponds to stage 3A chronic kidney disease andmoderate B renal impairment according to the present invention generallycorresponds to stage 3B chronic kidney disease. Therefore, the methodsand uses of SGLT-2 inhibitors, particularly empagliflozin, in thecontext of the present invention and applied to patients having renalimpairment as defined herein also apply to patients having thecorresponding stage of chronic kidney disease.

In some aspects, renal disease, renal dysfunction, or insufficiency orimpairment of renal function (including mild, moderate and/or severerenal impairment) may also be suggested (if not otherwise noted) byelevated serum creatinine levels (e.g. serum creatinine levels above theupper limit of normal for their age, e.g. ≥130-150 μmol/l, or ≥1.5 mg/dl(≥136 μmol/l) in men and ≥1.4 mg/dl (≥124 μmol/l) in women) or abnormalcreatinine clearance (e.g. glomerular filtration rate (GFR) ≤30-60ml/min).

In some further aspects, mild renal impairment may be also suggested (ifnot otherwise noted) by a creatinine clearance of 50-80 ml/min(approximately corresponding to serum creatine levels of ≤1.7 mg/dL inmen and ≤1.5 mg/dL in women); moderate renal impairment may be e.g.suggested (if not otherwise noted) by a creatinine clearance of 30-50ml/min (approximately corresponding to serum creatinine levels of >1.7to ≤3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women); and severe renalimpairment may be e.g. suggested (if not otherwise noted) by acreatinine clearance of <30 ml/min (approximately corresponding to serumcreatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women).Patients with end-stage renal disease require dialysis (e.g.hemodialysis or peritoneal dialysis).

Albuminuria stages may be for example classified as disclosed hereinand/or by urine albumin creatinine ratio (such as usually UACR ≥30 mg/g,in some instances ≥20 μg/min albumin excretion rate), such as e.g.microalbuminuria may be for example classified by UACR 30-300 mg/g (insome instances 20-200 μg/min) or, in another embodiment, by UACR 30-200mg/g, and/or macroalbuminuria may be for example classified by UACR >300mg/g (in some instances >200 μg/min), or, in another embodiment, byUACR >200 mg/g. Very high UACR ≥2000 mg/g may be classified asnephrotic.

Accordingly, in one embodiment, the present invention provides a methodof treating type 2 diabetes in patient comprising administeringempagliflozin to the patient, wherein the patient has moderate renalimpairment (or CKD stage 3). In one embodiment, the patient has moderateA renal impairment (or CKD stage 3A). In one embodiment, the patient hasmoderate B renal impairment (or CKD stage 3B).

In a further embodiment, the present invention provides a method forimproving glycemic control in a patient with type 2 diabetes comprisingadministering empagliflozin to the patient, wherein the patient hasmoderate renal impairment (or CKD stage 3). In one embodiment, thepatient has moderate A renal impairment (or CKD stage 3A). In oneembodiment, the patient has moderate B renal impairment (or CKD stage3B).

In one aspect, in a method of the present invention, the renal functionof a patient is monitored during the treatment with empagliflozin, forexample by measuring the eGFR of the patient. For example, the renalfunction of a patient is monitored during the treatment withempagliflozin if the eGFR of the patient is below 60 ml/min/1.73 m² orbelow 45 ml/min/1.73 m². In one aspect, in such a method, the treatmentwith empagliflozin is discontinued if the eGFR of the patient fallsbelow a certain value, for example below 30 ml/min/1.73 m² or below 45ml/min/1.73 m².

In one embodiment, diabetes patients within the meaning of thisinvention may include patients who have not previously been treated withan antidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In anotherembodiment, diabetes patients within the meaning of this invention mayinclude patients with advanced or late stage type 2 diabetes mellitus(including patients with failure to conventional antidiabetic therapy),such as e.g. patients with inadequate glycemic control on one, two ormore conventional oral and/or non-oral antidiabetic drugs as definedherein, such as e.g. patients with insufficient glycemic control despite(mono-)therapy with metformin, a thiazolidinedione (particularlypioglitazone), a sulphonylurea, a glinide, GLP-1 or GLP-1 analogue,insulin or insulin analogue, or an α-glucosidase inhibitor, or despitedual combination therapy with metformin/sulphonylurea,metformin/thiazolidinedione (particularly pioglitazone),sulphonylurea/α-glucosidase inhibitor, pioglitazone/sulphonylurea,metformin/insulin, pioglitazone/insulin or sulphonylurea/insulin. Thus,in an embodiment, the therapies described herein may be used in patientsexperienced with therapy, e.g. with conventional oral and/or non-oralantidiabetic mono- or dual or triple combination medication as mentionedherein.

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those diabetes patients (especially type 2 diabetes) with advanced ageand/or with advanced diabetes disease, such as e.g. patients on insulintreatment, patients on triple antidiabetic oral therapy, patients withpre-existing cardiovascular events and/or patients with advanced diseaseduration (e.g. >/=5 to 10 years).

The present invention further relates to a pharmaceutical compositioncomprising a certain SGLT-2 inhibitor as defined herein, empagliflozin,for use in the therapies described herein.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans.In the scope of this invention adult patients are preferably humans ofthe age of 18 years or older. Also in the scope of this invention,patients are adolescent humans, i.e. humans of age 10 to 17 years,preferably of age 13 to 17 years. It is assumed that in a adolescentpopulation the administration of the pharmaceutical compositionaccording to the invention a very good HbA1c lowering and a very goodlowering of the fasting plasma glucose can be seen. In addition it isassumed that in an adolescent population, in particular in overweightand/or obese patients, a pronounced weight loss can be observed.

As described hereinbefore by the administration of the pharmaceuticalcomposition according to this invention and in particular in view of thehigh SGLT2 inhibitory activity of the SGLT2 inhibitors therein,excessive blood glucose is excreted through the urine of the patient, sothat no gain in weight or even a reduction in body weight may result.Therefore, a treatment or prophylaxis according to this invention isadvantageously suitable in those patients in need of such treatment orprophylaxis who are diagnosed of one or more of the conditions selectedfrom the group consisting of overweight and obesity, in particular classI obesity, class II obesity, class III obesity, visceral obesity andabdominal obesity. In addition a treatment or prophylaxis according tothis invention is advantageously suitable in those patients in which aweight increase is contraindicated. The pharmaceutical composition aswell as the methods according to the present invention allow a reductionof the HbA1c value to a desired target range, for example <7% andpreferably <6.5%, for a higher number of patients and for a longer timeof therapeutic treatment compared with a corresponding monotherapy or atherapy using only two of the combination partners.

The pharmaceutical composition according to this invention and inparticular the SGLT2 inhibitor therein exhibits a very good efficacywith regard to glycemic control, in particular in view of a reduction offasting plasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin (HbA1c). By administering a pharmaceutical compositionaccording to this invention, a reduction of HbA1c equal to or greaterthan preferably 0.5%, even more preferably equal to or greater than 1.0%can be achieved and the reduction is particularly in the range from 1.0%to 2.0%.

Furthermore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   (a) a fasting blood glucose or serum glucose concentration greater    than 100 mg/dL, in particular greater than 125 mg/dL;-   (b) a postprandial plasma glucose equal to or greater than 140    mg/dL;-   (c) an HbA1c value equal to or greater than 6.5%, in particular    equal to or greater than 7.0%, especially equal to or greater than    7.5%, even more particularly equal to or greater than 8.0%.

The present invention also discloses the use of the pharmaceuticalcomposition for improving glycemic control in patients having type 1 ortype 2 diabetes or showing first signs of pre-diabetes. Thus, theinvention also includes diabetes prevention. If therefore apharmaceutical composition according to this invention is used toimprove the glycemic control as soon as one of the above-mentioned signsof pre-diabetes is present, the onset of manifest type 2 diabetesmellitus can be delayed or prevented.

Furthermore, the pharmaceutical composition according to this inventionis particularly suitable in the treatment of patients with insulindependency, i.e. in patients who are treated or otherwise would betreated or need treatment with an insulin or a derivative of insulin ora substitute of insulin or a formulation comprising an insulin or aderivative or substitute thereof. These patients include patients withdiabetes type 2 and patients with diabetes type 1.

Therefore, according to a preferred embodiment of the present invention,there is provided a method for improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patient in need thereof whois diagnosed with impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG) with insulin resistance, with metabolic syndromeand/or with type 2 or type 1 diabetes mellitus characterized in that anSGLT2 inhibitor as defined hereinbefore and hereinafter is administeredto the patient.

According to another preferred embodiment of the present invention,there is provided a method for improving glycemic control in patients,in particular in adult patients, with type 2 diabetes mellitus as anadjunct to diet and exercise.

It can be found that by using a pharmaceutical composition according tothis invention, an improvement of the glycemic control can be achievedeven in those patients who have insufficient glycemic control inparticular despite treatment with an antidiabetic drug, for exampledespite maximal recommended or tolerated dose of oral monotherapy withmetformin. A maximal recommended dose with regard to metformin is forexample 2000 mg per day or 850 mg three times a day or any equivalentthereof.

Therefore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   (a) insufficient glycemic control with diet and exercise alone;-   (b) insufficient glycemic control despite oral monotherapy with    metformin, in particular despite oral monotherapy at a maximal    tolerated dose of metformin;-   (c) insufficient glycemic control despite oral monotherapy with    another antidiabetic agent, in particular despite oral monotherapy    at a maximal tolerated dose of the other antidiabetic agent.

The lowering of the blood glucose level by the administration of anSGLT2 inhibitor according to this invention is insulin-independent.Therefore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   -   insulin resistance,    -   hyperinsulinemia,    -   pre-diabetes,    -   type 2 diabetes mellitus, particular having a late stage type 2        diabetes mellitus,    -   type 1 diabetes mellitus.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   (a) obesity (including class I, II and/or III obesity), visceral    obesity and/or abdominal obesity,-   (b) triglyceride blood level ≥150 mg/dL,-   (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50    mg/dL in male patients,-   (d) a systolic blood pressure ≥130 mm Hg and a diastolic blood    pressure ≥85 mm Hg,-   (e) a fasting blood glucose level ≥100 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance(IGT), impaired fasting blood glucose (IFG), with insulin resistanceand/or with metabolic syndrome suffer from an increased risk ofdeveloping a cardiovascular disease, such as for example myocardialinfarction, coronary heart disease, heart insufficiency, thromboembolicevents.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients after organtransplantation, in particular those patients who are diagnosed havingone or more of the following conditions

-   (a) a higher age, in particular above 50 years,-   (b) male gender;-   (c) overweight, obesity (including class I, II and/or III obesity),    visceral obesity and/or abdominal obesity,-   (d) pre-transplant diabetes,-   (e) immunosuppression therapy.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions:

-   (a) hyponatremia, in particular chronical hyponatremia;-   (b) water intoxication;-   (c) water retention;-   (d) plasma sodium concentration below 135 mmol/L.    The patient may be a diabetic or non-diabetic mammal, in particular    human.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions:

-   (a) high serum uric acid levels, in particular greater than 6.0    mg/dL (357 μmol/L);-   (b) a history of gouty arthritis, in particular recurrent gouty    arthritis;-   (c) kidney stones, in particular recurrent kidney stones;-   (d) a high propensity for kidney stone formation.

In certain embodiments, the patients which may be amenable to thetherapies of this invention may have or are at-risk of one or more ofthe following diseases, disorders or conditions: type 1 diabetes, type 2diabetes, impaired glucose tolerance (IGT), impaired fasting bloodglucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptivehyperglycemia, latent autoimmune diabetes in adults (LADA), overweight,obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia,hypertension, atherosclerosis, endothelial dysfunction, osteoporosis,chronic systemic inflammation, non alcoholic fatty liver disease(NAFLD), polycystic ovarian syndrome, metabolic syndrome, nephropathy,micro- or macroalbuminuria, proteinuria, retinopathy, cataracts,neuropathy, learning or memory impairment, neurodegenerative orcognitive disorders, cardiovascular diseases, tissue ischaemia, diabeticfoot or ulcus, atherosclerosis, hypertension, endothelial dysfunction,myocardial infarction, acute coronary syndrome, unstable anginapectoris, stable angina pectoris, peripheral arterial occlusive disease,cardiomyopathy (including e.g. uremic cardiomyopathy), heart failure,cardiac hypertrophy, heart rhythm disorders, vascular restenosis,stroke, (renal, cardiac, cerebral or hepatic) ischemia/reperfusioninjuries, (renal, cardiac, cerebral or hepatic) fibrosis, (renal,cardiac, cerebral or hepatic) vascular remodeling; a diabetic disease,especially type 2 diabetes, mellitus may be preferred (e.g. asunderlying disease).

In a further embodiment, the patients which may be amenable to thetherapies of this invention have a diabetic disease, especially type 2diabetes mellitus, and may have or are at-risk of one or more otherdiseases, disorders or conditions, such as e.g. selected from thosementioned immediately above.

Within the scope of the present invention it has now been found thatcertain SGLT-2 inhibitors as defined herein, optionally in combinationwith one or more other therapeutic substances (e.g. selected from thosedescribed herein), as well as pharmaceutical combinations, compositionsor combined uses according to this invention of such SGLT-2 inhibitorsas defined herein have properties, which make them suitable for thepurpose of this invention and/or for fulfilling one or more of aboveneeds.

The present invention thus relates to a certain SGLT-2 inhibitor asdefined herein, preferably empagliflozin, for use in the therapiesdescribed herein.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

A pharmaceutical composition according to this invention is particularlysuitable in the long term treatment or prophylaxis of the diseasesand/or conditions as described hereinbefore and hereinafter, inparticular in the long term glycemic control in patients with type 2diabetes mellitus.

The term “long term” as used hereinbefore and hereinafter indicates atreatment of or administration in a patient within a period of timelonger than 12 weeks, preferably longer than 25 weeks, even morepreferably longer than 1 year.

Therefore, a particularly preferred embodiment of the present inventionprovides a method for therapy, preferably oral therapy, for improvement,especially long term improvement, of glycemic control in patients withtype 2 diabetes mellitus, especially in patients with late stage type 2diabetes mellitus, in particular in patients additionally diagnosed ofoverweight, obesity (including class I, class II and/or class IIIobesity), visceral obesity and/or abdominal obesity.

It will be appreciated that the amount of the pharmaceutical compositionaccording to this invention to be administered to the patient andrequired for use in treatment or prophylaxis according to the presentinvention will vary with the route of administration, the nature andseverity of the condition for which treatment or prophylaxis isrequired, the age, weight and condition of the patient, concomitantmedication and will be ultimately at the discretion of the attendantphysician. In general, however, the SGLT2 inhibitor according to thisinvention is included in the pharmaceutical composition or dosage formin an amount sufficient that by its administration the glycemic controlin the patient to be treated is improved.

For the treatment of hyperuricemia or hyperuricemia associatedconditions the SGLT2 inhibitor according to this invention is includedin the pharmaceutical composition or dosage form in an amount sufficientthat is sufficient to treat hyperuricemia without disturbing thepatient's plasma glucose homeostasis, in particular without inducinghypoglycemia.

For the treatment or prevention of kidney stones the SGLT2 inhibitoraccording to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that is sufficient totreat or prevent kidney stones without disturbing the patient's plasmaglucose homeostasis, in particular without inducing hypoglycemia.

For the treatment of hyponatremia and associated conditions the SGLT2inhibitor according to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that is sufficient totreat hyponatremia or the associated conditions without disturbing thepatient's plasma glucose homeostasis, in particular without inducinghypoglycemia.

In the following preferred ranges of the amount of the SGLT2 inhibitorto be employed in the pharmaceutical composition and the methods anduses according to this invention are described. These ranges refer tothe amounts to be administered per day with respect to an adult patient,in particular to a human being, for example of approximately 70 kg bodyweight, and can be adapted accordingly with regard to an administration2, 3, 4 or more times daily and with regard to other routes ofadministration and with regard to the age of the patient. Within thescope of the present invention, the pharmaceutical composition ispreferably administered orally. Other forms of administration arepossible and described hereinafter. Preferably the one or more dosageforms comprising the SGLT2 inhibitor is oral or usually well known.

In general, the amount of the SGLT2 inhibitor in the pharmaceuticalcomposition and methods according to this invention is preferably theamount usually recommended for a monotherapy using said SGLT2 inhibitor.

The preferred dosage range of the SGLT2 inhibitor is in the range from0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferablyfrom 1 to 50 mg per day. In one aspect, a preferred dosage of the SGLT2inhibitor empagliflozin is 10 mg or 25 mg per day. The oraladministration is preferred. Therefore, a pharmaceutical composition maycomprise the hereinbefore mentioned amounts, in particular from 1 to 50mg or 1 to 25 mg. Particular dosage strengths (e.g. per tablet orcapsule) are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50 mgof the SGLT2 inhibitor, in particular empagliflozin. In one aspect, apharmaceutical composition comprises 10 mg or 25 mg of empagliflozin.The application of the active ingredient may occur up to three times aday, preferably one or two times a day, most preferably once a day.

A pharmaceutical composition which is present as a separate or multipledosage form, preferably as a kit of parts, is useful in combinationtherapy to flexibly suit the individual therapeutic needs of thepatient.

According to a first embodiment a preferred kit of parts comprises acontainment containing a dosage form comprising the SGLT2 inhibitor andat least one pharmaceutically acceptable carrier.

A further aspect of the present invention is a manufacture comprisingthe pharmaceutical composition being present as separate dosage formsaccording to the present invention and a label or package insertcomprising instructions that the separate dosage forms are to beadministered in combination or alternation.

According to a first embodiment a manufacture comprises (a) apharmaceutical composition comprising a SGLT2 inhibitor according to thepresent invention and (b) a label or package insert which comprisesinstructions that the medicament is to be administered.

The desired dose of the pharmaceutical composition according to thisinvention may conveniently be presented in a once daily or as divideddose administered at appropriate intervals, for example as two, three ormore doses per day.

The pharmaceutical composition may be formulated for oral, rectal,nasal, topical (including buccal and sublingual), transdermal, vaginalor parenteral (including intramuscular, sub-cutaneous and intravenous)administration in liquid or solid form or in a form suitable foradministration by inhalation or insufflation. Oral administration ispreferred. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy. All methods include the stepof bringing into association the active ingredient with one or morepharmaceutically acceptable carriers, like liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets,granules, fine granules, powders, capsules, caplets, soft capsules,pills, oral solutions, syrups, dry syrups, chewable tablets, troches,effervescent tablets, drops, suspension, fast dissolving tablets, oralfast-dispersing tablets, etc.

The pharmaceutical composition and the dosage forms preferably comprisesone or more pharmaceutical acceptable carriers which must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.Examples of pharmaceutically acceptable carriers are known to the oneskilled in the art.

Pharmaceutical compositions suitable for oral administration mayconveniently be presented as discrete units such as capsules, includingsoft gelatin capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution, a suspension or as an emulsion, for example as syrups,elixirs or self-emulsifying delivery systems (SEDDS). The activeingredients may also be presented as a bolus, electuary or paste.Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, fillers, lubricants, disintegrants,or wetting agents. The tablets may be coated according to methods wellknown in the art. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups orelixirs, or may be presented as a dry product for constitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, emulsifyingagents, non-aqueous vehicles (which may include edible oils), orpreservatives.

The pharmaceutical composition according to the invention may also beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredients may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound(s) with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

The pharmaceutical compositions and methods according to this inventionshow advantageous effects in the treatment and prevention of thosediseases and conditions as described hereinbefore. Advantageous effectsmay be seen for example with respect to efficacy, dosage strength,dosage frequency, pharmacodynamic properties, pharmacokineticproperties, fewer adverse effects, convenience, compliance, etc.

Methods for the manufacture of SGLT2 inhibitors according to thisinvention and of prodrugs thereof are known to the one skilled in theart. Advantageously, the compounds according to this invention can beprepared using synthetic methods as described in the literature,including patent applications as cited hereinbefore. Preferred methodsof manufacture are described in the WO 2006/120208 and WO 2007/031548.With regard to empagliflozin an advantageous crystalline form isdescribed in the international patent application WO 2006/117359 whichhereby is incorporated herein in its entirety.

The active ingredients may be present in the form of a pharmaceuticallyacceptable salt. Pharmaceutically acceptable salts include, withoutbeing restricted thereto, such as salts of inorganic acid likehydrochloric acid, sulfuric acid and phosphoric acid; salts of organiccarboxylic acid like oxalic acid, acetic acid, citric acid, malic acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acidand glutamic acid and salts of organic sulfonic acid likemethanesulfonic acid and p-toluenesulfonic acid. The salts can be formedby combining the compound and an acid in the appropriate amount andratio in a solvent and decomposer. They can be also obtained by thecation or anion exchange from the form of other salts.

The active ingredients or a pharmaceutically acceptable salt thereof maybe present in the form of a solvate such as a hydrate or alcohol adduct.

Pharmaceutical compositions or combinations for use in these therapiescomprising the SGLT-2 inhibitor as defined herein optionally togetherwith one or more other active substances are also contemplated.

Further, the present invention relates to the SGLT-2 inhibitors,optionally in combination with one, two or more further active agents,each as defined herein, for use in the therapies as described herein.

Further, the present invention relates to the use of the SGLT-2inhibitors, optionally in combination with one, two or more furtheractive agents, each as defined herein, for preparing pharmaceuticalcompositions which are suitable for the treatment and/or preventionpurposes of this invention.

The present invention further relates to a pharmaceutical compositioncomprising a certain SGLT-2 inhibitor as defined herein, preferablyempagliflozin, and metformin and/or a DPP-4 inhibitor, for examplelinagliptin, for use in the therapies described herein.

The present invention further relates to a combination comprising acertain SGLT-2 inhibitor (particularly empagliflozin) and one or moreother antidiabetics selected from the group consisting of metformin, asulphonylurea, nateglinide, repaglinide, a thiazolidinedione, analpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or aGLP-1 analogue and a DPP-4 inhibitor, particularly for simultaneous,separate or sequential use in the therapies described herein.

The present invention further relates to a method for treating and/orpreventing metabolic diseases, especially type 2 diabetes mellitusand/or conditions related thereto (e.g. diabetic complications)comprising the combined (e.g. simultaneous, separate or sequential)administration of an effective amount of one or more other antidiabeticsselected from the group consisting of metformin, a sulphonylurea,nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma-agonist, analpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or aGLP-1 analogue and a DPP-4 inhibitor, to the patient (particularly humanpatient) in need thereof, such as e.g. a patient as described herein.

The present invention further relates to therapies or therapeuticmethods described herein, such as e.g. a method for treating and/orpreventing metabolic diseases, especially type 2 diabetes mellitusand/or conditions related thereto (e.g. diabetic complications),comprising administering a therapeutically effective amount ofempagliflozin and, optionally, one or more other therapeutic agents,such as e.g. antidiabetics selected from the group consisting ofmetformin, a sulphonylurea, nateglinide, repaglinide, athiazolidinedione, a PPAR-gamma-agonist, an alpha-glucosidase inhibitor,insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4inhibitor, to the patient (particularly human patient) in need thereof,such as e.g. a patient as described herein.

Within this invention it is to be understood that the combinations,compositions or combined uses according to this invention may envisagethe simultaneous, sequential or separate administration of the activecomponents or ingredients.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits) and uses, such as e.g. the simultaneous,sequential or separate use of the components or ingredients.

The combined administration of this invention may take place byadministering the active components or ingredients together, such ase.g. by administering them simultaneously in one single or in twoseparate formulations or dosage forms. Alternatively, the administrationmay take place by administering the active components or ingredientssequentially, such as e.g. successively in two separate formulations ordosage forms.

For the combination therapy of this invention the active components oringredients may be administered separately (which implies that they areformulated separately) or formulated altogether (which implies that theyare formulated in the same preparation or in the same dosage form).Hence, the administration of one element of the combination of thepresent invention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

The present invention further relates to a certain SGLT-2 inhibitor asdefined herein, preferably empagliflozin, in combination with metformin,for use in the therapies described herein.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

For children 10 to 16 years of age, the recommended starting dose ofmetformin is 500 mg given once daily. If this dose fails to produceadequate results, the dose may be increased to 500 mg twice daily.Further increases may be made in increments of 500 mg weekly to amaximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3divided doses). Metformin may be administered with food to decreasenausea.

An example of a DPP-4 inhibitor is linagliptin, which is usually givenin a dosage of 5 mg per day. Therefore, a pharmaceutical composition maycomprise 5 mg linagliptin in addition to the SGLT2 inhibitor, inparticular empagliflozin in an amount of 10 mg or 25 mg.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg),or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg)once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES Example 1: Empagliflozin in Patients with Type 2 DiabetesMellitus (T2DM) and Renal Impairment (RI)

A Phase III trial investigated the efficacy and safety of empagliflozin(EMPA) as add-on to existing therapy for 52 weeks in patients with T2DMand RI. Patients with mild RI (eGFR [MDRD equation]≥60 to <90mL/min/1.73 m²; n=290; mean age 62.6 years; mean BMI 31.5 kg/m²)received EMPA 10 or 25 mg qd or placebo (PBO). Patients with moderate RI(eGFR ≥30 to <60 mL/min/1.73 m²; n=374; mean age 64.9 years; mean BMI30.2 kg/m²) received EMPA 25 mg qd or PBO. The primary endpoint waschange from baseline in HbA_(1c) at week 24. Exploratory endpointsincluded changes from baseline in fasting plasma glucose (FPG), weightand blood pressure (BP) at week 24 (FIG. 1).

EMPA significantly reduced HbA_(1c) vs PBO at week 24. Further analysesshowed significant reductions in FPG, weight and BP. At week 24, adverseevents (AEs) were reported by 79.6%, 75.4% and 72.7% of all patients(including an exploratory group with severe RI [n=74] on EMPA 25 mg orPBO) on EMPA 10 mg, 25 mg and PBO, respectively. Hypoglycemia (plasmaglucose ≤70 mg/dL and/or requiring assistance) was reported in 23.5% ofpatients on EMPA 10 mg, 22.1% on EMPA 25 mg and 22.9% on PBO. AEsconsistent with urinary tract infection were reported in 10.2% ofpatients on EMPA 10 mg, 9.0% on EMPA 25 mg and 8.2% on PBO. AEsconsistent with genital infection were reported in 6.1% of patients onEMPA 10 mg, 2.5% on EMPA 25 mg and 1.3% on PBO.

To conclude, in patients with T2DM and mild or moderate RI, EMPA reducedHbA_(1c), weight, and BP vs PBO, and was well tolerated.

The primary endpoint was also analysed for patients with moderate A andmoderate B renal impairment. For the patients with moderate A renalimpairment, the difference to placebo for the adjusted mean change inHbA_(1c) from baseline at Week 24 was −0.46% (95% CI: −0.66, −0.27). Forthe patients with moderate B renal impairment, the difference to placebofor the adjusted mean change in HbA_(1c) from baseline at Week 24 was−0.39% (95% CI: −0.58, −0.19).

Example 2: Mixed Effects Modeling to Quantify the Effect ofEmpagliflozin Exposure on the Renal Glucose Threshold in Patients withType 2 Diabetes Mellitus

Empagliflozin, a selective and potent SGLT2 inhibitor, reduces renalglucose reabsorption by lowering the renal threshold for glucose(RT_(G)) leading to increased urinary glucose excretion (UGE) anddecreased plasma glucose (PG) in patients with type 2 diabetes mellitus(T2DM). This analysis aimed to quantify the impact of empagliflozin onRT_(G) by characterizing the relationship between empagliflozin exposureand UGE in patients with T2DM using nonlinear mixed-effects modeling.

A pharmacokinetic (PK)-pharmacodynamic (PD) model was developed usingUGE, PG, PK and estimated glomerular filtration rate (eGFR) data fromthree Phase I/II trials (N=223; placebo, empagliflozin 1 to 100 mg oncedaily [QD]). The model assumed that when PG>RT_(G), UGE increased withincreasing PG and eGFR; and when PG≤RT_(G) slight glucose leakage intourine occurred (estimated as fraction reabsorbed [FRAC]). Reabsorptionwas estimated by a nonlinear function parameterized in terms of maximumreabsorbed glucose concentration (G_(max)) and PG concentration to reachhalf maximum transport (K_(m)). Maximum inhibitory effect (I_(max)) andhalf maximal inhibitory concentration (IC₅₀) described inhibition ofrenal glucose absorption. RT_(G) was calculated as the differencebetween maximum reabsorption (including drug effect) and K_(M). Themodel was evaluated via bootstrap and external predictive check of anempagliflozin renal impairment study.

The parameter estimates (95% CI) were G_(max): 374 (347, 391) mg/dL;K_(m): 144 (113, 163) mg/dL; I_(max): 0.559 (0.545, 0.607); IC₅₀: 5.28(3.53, 8.91) nmol/L; FRAC: 0.999 (0.998, 0.999).

The calculated RT_(G) for placebo was 230 mg/dL. RT_(G) decreased withincreasing empagliflozin concentration; doses of 1, 5, 10, and 25 mgyielded RT_(G) values of 100.5, 43.8, 33.1, and 26.0 mg/dL,respectively. External predictive check demonstrated unbiased predictionof UGE across a range of eGFR values (end-stage renal disease to normalrenal function). Simulation indicated that for 10 and 25 mg QD, >50% and90% of subjects, respectively, maintained steady-state empagliflozinconcentrations >IC₈₀ for RT_(G) lowering over the dosing interval.

Example 3: Pharmacokinetics and Pharmacodynamics of Empagliflozin inSubjects with Renal Impairment Subjects.

Male and female subjects aged 18 to 75 years weighing at least 45 kg(females only) and with a body mass index (BMI) of 18 to 34 kg/m² wereeligible for inclusion in this study. Participants with normal renalfunction (eGFR >90 mL/min/1.73 m²; control) were required to have T2DM.Patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²),moderate renal impairment (eGFR 30-59 mL/min/1.73 m²), severe renalimpairment (eGFR <30 aim in/1.73 m²) or renal failure/ESRD (requiringdialysis) did not need to have T2DM. eGFR was calculated using theModification of Diet in Renal Disease (MDRD) formula: 186×serumcreatinine^(−1.154)×age^(−0.203)×[0.742 if female].

Subjects were excluded from the study if they had recently participatedin a study (multiple-dose: within 2 months; single-dose: within 1month), were abusing alcohol (males >60 g/day; females >40 g/day) ordrugs, had donated >100 mL blood in the previous 4 weeks, were takingconcomitant medications known to inhibit or induce p-glycoprotein orcytochrome P450 3A, or had any medical or laboratory results deviatingfrom normal and of clinical relevance.

Subjects with renal impairment were excluded if they had significantdiseases other than renal impairment or T2DM, including moderate andsevere concurrent hepatic impairment, hemoglobin <8 g/dL indicatingsevere renal anemia (erythropoietin could be used to maintain hemoglobinlevels), and intake of drugs with a long half-life (>24 h) within theprevious month (or within 10 half-lives of that drug, if longer), exceptfor those being taken for the treatment of renal disease.

The investigators, in cooperation with nephrology centers, aimed torecruit 8 subjects for every group. Subjects with normal renal functionwere matched to those in the renal impairment groups by age (±5 years)and weight (±15%), where possible.

Study Design.

This 2-center, open-label, parallel-group study was undertaken to assessthe effect of renal function on the pharmacokinetics, pharmacodynamics,and safety of a single 50 mg dose of empagliflozin. Subjects werescreened for eligibility up to 21 days prior to study drugadministration. Following an overnight fast, subjects were admitted tothe research unit and received a 50 mg dose of empagliflozin with 240 mLof water (day 1). Water was allowed ad libitum except for 1 h before and1 h after study drug administration. Following medical surveillance for24 h, subjects were discharged (day 2) and were monitored as outpatientsuntil they attended an end-of-study examination (within 14 days afterthe last trial procedure).

Pharmacokinetic Endpoints.

One objective of the study was to determine the effect of renalimpairment on the relative bioavailability of empagliflozin, based onthe primary endpoints of AUC_(0-∞) and C_(max). Secondarypharmacokinetic endpoints included: t_(max), t_(1/2), fe₀₋₉₆,CL_(R,0-96), and plasma protein binding of empagliflozin.

Pharmacodynamic Endpoint.

The pharmacodynamic endpoint of the study was the cumulative amount ofUGE over a 24 h period following drug administration (UGE₀₋₂₄), relativeto baseline, with a baseline measurement obtained over 24 h precedingadministration of study drug.

Sample Collection and Analysis.

Approximately 124 mL of blood was taken from every subject over thecourse of the study for clinical laboratory tests (44 mL),pharmacokinetic assessments (50 mL), and determination of proteinbinding (30 mL). Blood samples for clinical laboratory testing werecollected after subjects had fasted for at least 10 h.

For quantification of empagliflozin plasma concentrations 2.7 mL ofblood was taken from a forearm vein in a K₃-EDTA (tripotassiumethylenediaminetetraacetic acid)-anticoagulant blood drawing tube atpre-dose and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36,48, 72, and 96 h post-dose. Within 30 min of collection, the sampleswere centrifuged for 10 min at 2000-4000 g and 4-8° C. The EDTA plasmaobtained was stored at −18° C. until it was shipped on dry ice foranalysis.

Urine was collected over 24 h prior to drug administration and at thefollowing intervals following drug administration: 0-4, 4-8, 8-12,12-24, 24-36, 36-48, 48-72, and 72-96 h. Urine containers were weighedempty and at the end of every sampling period and the difference wasrecorded as the urine volume (weight was set equal to volume, i.e. 1kg=1 L). Urine containers were refrigerated until 25 h after drugadministration and aliquots were stored at −18° C. until shipped on dryice for analysis.

Empagliflozin concentrations in plasma and urine were determined byvalidated high performance liquid chromatography, tandem massspectrometry (HPLC-MS/MS) assays. Empagliflozin and the internalstandard [¹³C₆]-empagliflozin were extracted from urine or plasma bysupported liquid extraction. After evaporation under nitrogen, theresidue was reconstituted and analyzed using liquid chromatography withMS/MS detection. The lower limit of quantification for empagliflozin inhuman plasma was 1.11 nmol/L, with linearity to 1110 nmol/L using asample volume of 0.15 mL, and in human urine was 4.44 nmol/L, withlinearity to 4440 nmol/L using a sample volume of 0.05 mL. For bothplasma and urine, results were calculated using peak area ratios andcalibration curves were created using weighted (1/x²) quadraticregression.

For determination of protein binding of empagliflozin, 10 mL blood wascollected at pre-dose, 1.5 and 3 h post-dose. Blood was centrifuged for10 min at 4000 g and 4° C., and the plasma was stored at −20° C. untilit was shipped on dry ice for analysis. The binding of empagliflozin andthe internal standard [¹³C₆]-empagliflozin to human plasma protein wasdetermined by equilibrium dialysis at 37° C. As a quality controlmeasure, protein binding analyses were performed using the pre-doseplasma samples.

Pharmacokinetic parameters were calculated using WinNonlin™ software(v5.01, Pharsight Corporation, Mountain View, Calif., USA). C_(max) andt_(max) values were directly determined from the plasma concentrationtime profiles of each subject. The apparent terminal rate constant(λ_(z)) was estimated from a regression of ln(C) versus time over theterminal log-linear drug disposition portion of the concentration-timeprofiles. The t_(1/2) was calculated as the quotient of ln(2) and λ_(z).Area under the plasma concentration-time curve to the last time point(AUC_(0-tz)) was calculated using the linear trapezoidal method forascending concentrations and the log trapezoidal method for descendingconcentrations. The AUC_(0-∞) value was estimated as the sum of AUC tothe last measured concentration, with the extrapolated area given by thequotient of the last measured concentration and λ_(z). The amount ofdrug (A_(e)) excreted unchanged in urine in each collection interval wasdetermined by the product of the urine concentration and the urinevolume. The fraction of the dose (f_(e)) that was excreted unchanged inurine was determined by the quotient of the sum of drug excreted overall dosing intervals and the dose administered. Renal clearance (CL_(R))was determined as the quotient of A_(e) over AUC. Cumulative UGE wascalculated using the glucose concentration measured in every urinesample collected from −24-0 h and 0-96 h after dosing. UGE (mg) wascalculated as follows: glucose concentration [mg/dL]×urine volume [dL]).Results are shown in FIGS. 2 to 6.

Statistical Analysis.

All subjects who provided at least one observation for at least oneprimary endpoint without any protocol violations relevant topharmacokinetic evaluation were included in the analysis of relativebioavailability (pharmacokinetic analysis set). All subjects with abaseline UGE value (0-24 h pre-dose) and a UGE value from 0-24 hpost-dose without any protocol violations relevant to UGE analysis wereincluded in the UGE analysis set. All safety analyses were performed onall subjects who received study drug (treated set). One objective of thestudy was to investigate the relative bioavailability of empagliflozinin subjects with normal renal function (R) compared with subjects withvarious degrees of renal impairment (T1-4), by presenting pointestimators (adjusted geometric mean [gMean] T/R ratios) of AUC_(0-∞) andC_(max) and their 2-sided 90% CIs. AUC_(0-∞) and C_(max) were analyzedusing an analysis of variance (ANOVA) model on the logarithmic scaleincluding a fixed effect corresponding to the renal function (normal,mild impairment, moderate impairment, severe impairment, or renalfailure/ESRD). The change in UGE 0-24 h from baseline after drugadministration was analyzed by an analysis of covariance (ANCOVA) modelincluding baseline UGE values as a continuous covariate, and a fixedeffect corresponding to the renal function. Descriptive statistics werecalculated for all pharmacokinetic and pharmacodynamic parameters.Safety analyses were descriptive in nature.

Example 4: Empagliflozin in Patients with Type 2 Diabetes Mellitus(T2DM) and Stage 3A, 3B and 4 Chronic Kidney Disease (CKD)

A Phase III trial investigated the efficacy and safety of empagliflozin(EMPA) as add-on to existing therapy for 52 weeks in patients with T2DMand CKD stage 3A, 3B and 4.

Patients with CKD stage 3A (eGFR [MDRD equation]≥45 to <60 ml/min/1.73m²; n=180; mean [SD] age 64.5 [8.0] years; mean [SD] BMI 30.5 [5.2]kg/m²), CKD stage 3B (eGFR 30 to <45 ml/min/1.73 m²; n=194; mean [SD]age 65.2 [9.0] years; mean [SD] BMI 30.0 [5.4] kg/m²) or CKD stage 4(eGFR ≥15 to <30 ml/min/1.73 m²; n=74; mean [SD] age 64.1 [11.1] years;mean [SD] BMI 30.4 [5.6] kg/m²) received EMPA 25 mg qd or PBO for 52weeks. In exploratory analyses, we assessed the long-term efficacy andsafety of EMPA, including changes from baseline in HbA_(1c), fastingplasma glucose (FPG), weight and systolic and diastolic blood pressure(SBP and DBP) at week 52 (FIG. 7).

EMPA 25 mg significantly reduced HbA_(1c) vs PBO at week 52 in patientswith CKD stage 3A and 3B (Table). EMPA 25 mg did not reduce HbA_(1c) inpatients with CKD stage 4 (Table). EMPA significantly reduced FPG,weight, SBP and DBP in patients with CKD stage 3A, and significantlyreduced FPG and weight in patients with CKD stage 3B (Table). Reductionsin FPG, weight and BP were observed in patients with CKD stage 4(Table). During 52 weeks' treatment, adverse events (AEs) were reportedby 86.8% and 79.8% of patients with CKD stage 3A on EMPA 25 mg and PBO,respectively, by 80.2% and 86.7% of patients with CKD stage 3B on EMPA25 mg and PBO, respectively, and by 91.9% and 83.8% of patients with CKDstage 4 on EMPA 25 mg and PBO, respectively. AEs consistent with volumedepletion were reported by 4.4% and 2.2% of patients with CKD stage 3Aon EMPA 25 mg and PBO, respectively, by 3.1% of patients with CKD stage3B on EMPA 25 mg or PBO, and by 5.4% patients with CKD stage 4 on EMPA25 mg or PBO. AEs consistent with urinary tract infection were reportedby 16.5% and 18.0% of patients with CKD stage 3A on EMPA 25 mg and PBO,respectively, by 16.7% and 13.3% of patients with CKD stage 3B on EMPA25 mg and PBO, respectively, and by 18.9% and 8.1% of patients with CKDstage 4 on EMPA 25 mg and PBO, respectively.

EMPA 25 mg for 52 weeks was associated with significant and clinicallymeaningful reductions in HbA_(1c) compared with placebo in patients withT2DM and CKD stage 3A or 3B. EMPA led to favourable reductions in bodyweight and BP in patients with T2DM and CKD stage 3A, 3B or 4.

Example 5: Treatment of Type 2 Diabetes Mellitus

Treating patients with type 2 diabetes mellitus with empagliflozin, inaddition to producing an acute improvement in the glucose metabolicsituation, prevents a deterioration in the metabolic situation in thelong term. This can be observed is patients are treated for a longerperiod, e.g. 3 months to 1 year or even 1 to 6 years, with a combinationaccording to the invention and are compared with patients who have beentreated with other antidiabetic and/or antiobesity medicaments. There isevidence of therapeutic success compared with other treatments if no oronly a slight increase in the fasting glucose and/or HbA1c value isobserved. Further evidence of therapeutic success is obtained if asignificantly smaller percentage of the patients treated with acombination according to the invention, compared with patients who havereceived another treatment, undergo a deterioration in the glucosemetabolic position (e.g. an increase in the HbA1c value to >6.5% or >7%)to the point where treatment with an (additional) oral antidiabeticmedicament or with insulin or with an insulin analogue is indicated.

Example 6: Treatment of Insulin Resistance

In clinical studies running for different lengths of time (e.g. 2 weeksto 12 months) the success of the treatment is checked using ahyperinsulinaemic euglycaemic glucose clamp study. A significant rise inthe glucose infusion rate at the end of the study, compared with theinitial value or compared with a placebo group, or a group given adifferent therapy, proves the efficacy of a treatment according to theinvention in the treatment of insulin resistance.

Example 7: Treatment of Hyperglycaemia

In clinical studies running for different lengths of time (e.g. 1 day to24 months) the success of the treatment in patients with hyperglycaemiais checked by determining the fasting glucose or non-fasting glucose(e.g. after a meal or a loading test with oGTT or a defined meal). Asignificant fall in these glucose values during or at the end of thestudy, compared with the initial value or compared with a placebo group,or a group given a different therapy, proves the efficacy of acombination treatment according to the invention in the treatment ofhyperglycaemia.

Example of Pharmaceutical Composition and Dosage Form

The following example of solid pharmaceutical compositions and dosageforms for oral administration serves to illustrate the present inventionmore fully without restricting it to the contents of the example.Further examples of compositions and dosage forms for oraladministration, are described in WO 2010/092126. The term “activesubstance” denotes empagliflozin according to this invention, especiallyits crystalline form as described in WO 2006/117359 and WO 2011/039107.

Tablets containing 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg of active substance2.5 mg/ 5 mg/ 10 mg/ 25 mg/ 50 mg/ Active per per per per per substancetablet tablet tablet tablet tablet Wet granulation active substance2.5000 5.000 10.00 25.00 50.00 Lactose 40.6250 81.250 162.50 113.00226.00 Monohydrate Microcrystalline 12.5000 25.000 50.00 40.00 80.00Cellulose Hydroxypropyl 1.8750 3.750 7.50 6.00 12.00 CelluloseCroscarmellose 1.2500 2.500 5.00 4.00 8.00 Sodium Purified Water q.s.q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 3.1250 6.250 12.50 10.0020.00 Cellulose Colloidal silicon 0.3125 0.625 1.25 1.00 2.00 dioxideMagnesium 0.3125 0.625 1.25 1.00 2.00 stearate Total core 62.5000125.000 250.00 200.00 400.00 Film Coating Film coating 2.5000 4.000 7.006.00 9.00 system Purified Water q.s. q.s. q.s. q.s. q.s. Total 65.000129.000 257.00 206.00 409.00

Details regarding the manufacture of the tablets, the activepharmaceutical ingredient, the excipients and the film coating systemare described in WO 2010/092126, in particular in the Examples 5 and 6,which hereby is incorporated herein in its entirety.

1.-26. (canceled)
 27. A method for improving glycemic control in apatient with type 2 diabetes mellitus comprising administeringempagliflozin to the patient if the eGFR of the patient is ≥45ml/min/1.73 m² and <60 ml/min/1.73 m², wherein empagliflozin isadministered orally in a total daily amount of 5 mg, 10 mg, 12.5 mg or25 mg, wherein the glycemic control in said patient is improved, anddiscontinuing empagliflozin if the eGFR of the patient falls below 45ml/min/1.73 m².
 28. The method according to claim 27, whereinempagliflozin is administered in a total daily amount of 5 mg.
 29. Themethod according to claim 27, wherein empagliflozin is administered in atotal daily amount of 10 mg.
 30. The method according to claim 27,wherein empagliflozin is administered in a total daily amount of 12.5mg.
 31. The method according to claim 27, wherein empagliflozin isadministered in a total daily amount of 25 mg.
 32. The method accordingto claim 27, further comprising administering metformin to the patient.33. A method for improving glycemic control in a patient with type 2diabetes mellitus comprising: a) assessing the renal function of apatient; b) administering empagliflozin to the patient if the eGFR ofthe patient is ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m², whereinempagliflozin is administered orally in a total daily amount of 5 mg, 10mg, 12.5 mg or 25 mg, wherein the glycemic control in said patient isimproved; c) discontinuing empagliflozin if the eGFR of the patientfalls below 45 ml/min/1.73 m².
 34. The method according to claim 33,wherein empagliflozin is administered in a total daily amount of 5 mg.35. The method according to claim 33, wherein empagliflozin isadministered in a total daily amount of 10 mg.
 36. The method accordingto claim 33, wherein empagliflozin is administered in a total dailyamount of 12.5 mg.
 37. The method according to claim 33, whereinempagliflozin is administered in a total daily amount of 25 mg.
 38. Themethod according to claim 33, further comprising administering metforminto the patient.
 39. A method of treating type 2 diabetes mellitus in apatient comprising administering empagliflozin to the patient if theeGFR of the patient is ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m²,wherein empagliflozin is administered orally in a total daily amount of5 mg, 10 mg, 12.5 mg or 25 mg, wherein the glycemic control in saidpatient is improved, and discontinuing empagliflozin if the eGFR of thepatient falls below 45 ml/min/1.73 m².
 40. The method according to claim39, wherein empagliflozin is administered in a total daily amount of 5mg.
 41. The method according to claim 39, wherein empagliflozin isadministered in a total daily amount of 10 mg.
 42. The method accordingto claim 39, wherein empagliflozin is administered in a total dailyamount of 12.5 mg.
 43. The method according to claim 39, whereinempagliflozin is administered in a total daily amount of 25 mg.
 44. Themethod according to claim 39, further comprising administering metforminto the patient.
 45. A method of treating type 2 diabetes mellituscomprising: a) assessing the renal function of a patient with type 2diabetes mellitus; b) administering empagliflozin to the patient if theeGFR of the patient is ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m²,wherein empagliflozin is administered orally in a total daily amount of5 mg, 10 mg, 12.5 mg or 25 mg, wherein the glycemic control in saidpatient is improved; c) discontinuing empagliflozin if the eGFR of thepatient falls below 45 ml/min/1.73 m².
 46. The method according to claim45, wherein empagliflozin is administered in a total daily amount of 5mg.
 47. The method according to claim 45, wherein empagliflozin isadministered in a total daily amount of 10 mg.
 48. The method accordingto claim 45, wherein empagliflozin is administered in a total dailyamount of 12.5 mg.
 49. The method according to claim 45, whereinempagliflozin is administered in a total daily amount of 25 mg.
 50. Themethod according to claim 45, further comprising administering metforminto the patient.